Human secretory glands are primarily divided into 2 types: apocrine and eccrine. Eccrine glands are in higher density on the soles of the feet and the forehead, followed by the palms and the cheeks. Apocrine sweat glands are located primarily in the axilla and urogenital regions. A third type of gland, referred to as apoeccrine glands, develop during puberty and are found primarily in the axillary and perianal areas. The apocrine and apoeccrine glands appear to be responsible for characteristic pheromonal odors, playing no part in temperature regulation.
Eccrine gland sweating is the primary means for body thermoregulation. The eccrine glands are found distributed all over the body in the dermis and epidermis, except for the margins of the limbs, sex organs, and ear drums. The sweat glands are innervated by the sympathetic nervous system and when the body's internal temperature exceeds the hypothalamic set point, activation of a sympathetic reflex causes an increase in sweat output. Evaporation of the sweat leads to a decrease in body temperature.
Hyperhidrosis
Hyperhidrosis, excessive sweating above that required for normal thermoregulation, is a condition that usually begins in childhood or adolescence. People affected with hyperhidrosis sweat more than is needed to cool the body to normal temperature. The disorder is diagnosed when sweating occurs under conditions when normally not expected or is excessive in response to emotional or thermal stimuli. This condition may be idiopathic (also known as primary or essential hyperhidrosis) or secondary to other diseases, metabolic disorders, febrile illnesses, or medication use. Hyperhidrosis affects about 1% of the population and includes people of both sexes and all races (reviewed in Cheshire and Freeman, 2003)
Primary hyperhidrosis is a far more frequent condition than secondary hyperhidrosis and is generally localized to the hands, feet, armpits or a combination of these. Tension and anxiety can elicit or aggravate sweating, but psychological/psychiatric disturbances are only rarely the cause of the disorder.
The primary sites of the body affected with hyperhidrosis, and the associated nomenclature, include:
The palms of the hand, known as palmer hyperhidrosis;
The soles of the feet, known as plantar hyperhidrosis;
The armpits, known as axillary hyperhidrosis;
The head, known as scalp and facial hyperhidrosis;
The trunk or thighs, known as truncal or thigh hyperhidrosis.
The lips, nose, and forehead, known as gustatory hyperhidrosis
Many individuals suffer from a combination of the above categories.
Excessive sweating causes embarrassment and discomfort and can lead to emotional distress and occupational disability for the subject. Additionally, hyperhidrosis can aggravate skin disorders like dermatitis and eczema and can result in loss of excess fluids from the body and electrolytes from the body.
Current Treatments for Hyperhidrosis
Current treatments for hyperhidrosis are symptomatic unless a physiological cause is identified. In patients with primary hyperhidrosis or for symptomatic treatment of heavy sweating in patients with secondary hyperhidrosis, not treatable otherwise, treatments include local injections of botulinum toxin, surgical removal of sweat glands, topical deodorants containing aluminum, systemic use of anti-cholinergic drugs and treatment with electric currents.
Botulinum toxin injections have been shown to have some efficacy in treating hyperhidrosis because of their anti-cholinergic effects at the neuromuscular junction and in the postganglionic sympathetic cholinergic nerves in the sweat glands. For example BOTOX® is indicated for the treatment of severe primary axillary hyperhidrosis. Agents such as BOTOX® are virtually useless for treating excess sweating in other parts of the body including the palms and back. U.S. Pat. No. 6,683,049 relates to a method of treating a excessive sweating with Botulinum toxin injections.
Sedative and/or anti-cholinergic drugs are effective at reducing sweating but the dosages required to achieve reduced sweating also result in adverse side effects including dryness of the mouth, constipation, blurred vision, decreased sexual ability, lack of appetite, nausea, somnolence, feeling of raised temperature and more. Most patients with localized or generalized hyperhidrosis can not tolerate them for extended periods.
Another treatment option is iontophoresis, which requires the application of a low intensity electric current (15-18 mA) applied to the palms and/or soles immersed in an electrolyte solution. The disadvantages are numerable and include the need for repeated treatments, high cost, recurrence of sweating after cessation, difficulty in applying to axillary region, and impracticality in treating diffuse hyperhidrosis of the face or the trunk/thigh region. The side effects include burning, electric shock, discomfort, tingling and skin irritation. Iontophoresis can be performed in the presence of therapeutic agents, as well. For example, International Patent Application Publication No. WO 00/54834 discloses a sweat control system providing iontophoresis of antiperspirant into a region of the body.
Surgical removal of sweat glands, including thoracoscopic sympathectomy for primary hyperhidrosis is an alternative treatment resulting in some relief to the subject, but can produce undesirable side effects including compensatory sweating.
Hypnosis and laser therapy are other treatment options resulting in some relief to the subject.
Certain pharmaceutical compositions useful for treating hyperhidrosis are known. For example, U.S. Pat. No. 5,730,964 teaches a method of treating sweat related conditions comprising administering orally or topically a therapeutically effective amount of a 5α-reductase inhibitor. U.S. Pat. No. 6,433,003 teaches a method for the treatment of hyperhidrosis comprising topically administering a composition comprising 0.25% to 6% of a glycopyrrolate compound. U.S. Pat. No. 5,258,388 teaches novel anti-cholinergic/anti-secretory agents useful as mydriatics and as antiperspirants.
US Patent Application Publication No. 20040192754 provides methods for treating idiopathic hyperhidrosis comprising administering to a patient compounds which reduce the activity of a 5-HT2C receptor. The composition comprising the 5-HT2C receptor antagonist can be concurrently administered with antiperspirants, tranquilizers and anti-cholinergic agents.
International Patent Application Publication No. WO 2004/040660 discloses compositions for treating skin wrinkles and hyperhidrosis comprising liminoid constituents, which inhibit acetylcholine release.
Oxybutynin
Oxybutynin (Ditropan®) is an anti-cholinergic agent useful in the treatment of urinary incontinence. Oxybutynin is usually administered in oral form but topical and transdermal compositions for achieving systemic therapeutic levels of the drug for the treatment of urinary incontinence are known in the art.
U.S. Pat. No. 5,900,250 teaches a method for the treatment of neurogenic bladder disorders comprising administering oxybutynin at a therapeutically effective rate to an area of skin; and simultaneously administering a permeation enhancer to the area of skin which is sufficient to substantially increase the permeability of the area to the drug. U.S. Pat. No. 4,747,845 teaches a transdermal synthetic resin matrix system for extended duration drug release and oxybutynin was listed as an agent that could be incorporated into such a system. A transdermal composition and transdermal patch comprising oxybutynin was shown to be effective in treating urinary incontinence (Dull, 2004). Oral oxybutynin was shown to be useful in treating the relatively rare syndrome of episodic hyperhidrosis with hypothermia (LeWitt, 1988).
Various permeation enhancers have been reported for transdermal systemic administration of oxybutynin. For example, U.S. Pat. Nos. 5,411,740; 5,500,222 and 5,614,211, each teach a monoglyceride or a mixture of monoglycerides of fatty acids as a permeation enhancer for an oxybutynin transdermal therapeutic system. U.S. Pat. No. 6,267,984 discloses skin permeation enhancer compositions comprising a monoglyceride and ethyl palmitate for transdermal delivery of oxybutynin. U.S. Pat. No. 5,747,065 discloses a combination of monoglycerides and lactate esters as a permeation enhancing mixture for oxybutynin.
U.S. Pat. No. 5,843,468 describes a dual permeation enhancer mixture of glycerol monolaurate and lauryl acetate for transdermal administration of, inter alia, oxybutynin. U.S. Pat. No. 6,004,578 disclose permeation enhancers selected from the group consisting of alkyl or aryl carboxylic acid esters of polyethyleneglycol monoalkyl ether, and polyethyleneglycol alkyl carboxymethyl ethers for transdermal drug delivery of, inter alia, oxybutynin. U.S. Pat. No. 6,562,368 discloses the use of hydroxide-releasing agent to increase the permeability of skin or mucosal tissue to transdermally administered oxybutynin
International Patent Application Publication No. WO 2005/107812 relates to a transdermal composition for enhanced systemic delivery of an anti-cholinergic agent, comprising a urea-containing compound in a carrier system
Tolterodine (Detrol®, Detrusitol®) is another anti-cholinergic agent indicated for the treatment of urinary difficulties, including frequent urination and inability to control urination. U.S. Pat. Nos. 6,517,864 and 7,008,637 teach the use of transdermally administered tolterodine as an anti-muscarinic agent for the treatment of incontinence.
Sulpiride (Modal®, Dolmatil®, Dogmatyl®, Sulpitil®) is a substituted benzamide neuroleptic agent used to treat stress, dizziness, nausea, vomiting, hypertension, irritable bowel syndrome and ulcer. U.S. Pat. No. 4,751,236 teaches the use of sulpiride for treating genital herpes; U.S. Pat. No. 5,908,853 teaches the use of a combination of an H2 agonist and sulpiride for treating erectile dysfunction.
The above disclosures neither teach nor suggest the topical administration of oxybutynin, tolterodine or a substituted benzamide medication to treat hyperhidrosis.
There remains an unmet need for a treatment for sweating and excess sweating including hyperhidrosis that is noninvasive, excludes undesirable side effects, is easy to administer and is cost effective to the patient.